This is an application to continue studies on the delineation of pathogenic mechanisms of SIVmac in infected rhesus macaques. Our earlier studies had suggested that the ability of the virus to cause disease in the lymphoid or the nervous system correlated with nucleotide sequences in the viral DNA that conferred tropism of the virus for CD4+ T cells (L) or (brain-specific?) macrophages (M), respectively; that mild disease was associated with early development of virus-inhibitory CD8+ cells; that severe disease correlated with an intense and prolonged early phase of immunological activation of infected CD4+ T cells; and that resurgence of viral replication occurred in infected animals that had developed immunological control over their infection. Experiments proposed in this application will test these hypotheses. 1. Whereas disease in the lymphoid system may be caused by both L- and M-tropic viruses, dementia can be caused only by a subclass of M-tropic viruses (AIM 1,3) and requires only incomplete or defective virus replication in CNS cells (AIM 1). Full-blown encephalopathy is a severe complication of dementia and occurs only when infected macrophages in the brain become immunologically activated, a state that renders these cells permissive for full expression of the virus life cycle (AIM 3). 2. If antiviral CD8+ cells are the main host defense against replication of L- and M-tropic viruses, then specific interference with the function of these cells should result in severe disease (AIDS or neurological) (AIM 1). 3. If severe disease and dissemination of infected cells to the CNS ("neuroinvasion") are a direct function of immunological activation of CD4+ T cells (which both L and M-tropic viruses infect), then immuno- intervention aimed at reducing the level of cellular activation should result in only mild disease and sparing of the CNS (AIM 2). 4. If resurgence of virus replication in infected immune animals is caused by CTL-escape variants, then such viruses, but not the original virus, should be able to replicate selectively in cultured autologous CD4+ T cells in the presence of CD8+ cells that inhibit the original virus. Our study on molecular immunopathogenesis of CNS disease will also be evaluated physiologically with assessment of cognitive and motor functions of the animals and also with a study to determine whether neurovirulence of the viruses correlates with non-neutralizing antibodies that enhance infection in macrophages.